SARS-CoV-2 spike protein–induced cell fusion activates the cGAS-STING pathway and the interferon response

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the unprecedented coronavirus disease 2019 (COVID-19) pandemic. Critical cases of COVID-19 are characterized by the production of excessive amounts of cytokines and extensive lung damage, which is partially caused by the fusion of SARS-CoV-2–infected pneumocytes. Here, we found that cell fusion caused by the SARS-CoV-2 spike (S) protein induced a type I interferon (IFN) response. This function of the S protein required its cleavage by proteases at the S1/S2 and the S2′ sites. We further showed that cell fusion damaged nuclei and resulted in the formation of micronuclei that were sensed by the cytosolic DNA sensor cGAS and led to the activation of its downstream effector STING. Phosphorylation of the transcriptional regulator IRF3 and the expression of IFNB , which encodes a type I IFN, were abrogated in cGAS-deficient fused cells. Moreover, infection with VSV-SARS-CoV-2 also induced cell fusion, DNA damage, and cGAS-STING–dependent expression of IFNB . Together, these results uncover a pathway underlying the IFN response to SARS-CoV-2 infection. Our data suggest a mechanism by which fused pneumocytes in the lungs of patients with COVID-19 may enhance the production of IFNs and other cytokines, thus exacerbating disease severity.

SARS-CoV-2 and the Nucleus

“…DNA damage response is quickly induced after SARS-CoV-2 infection but is swiftly suppressed in less than a day (77). This can be due to increased DNA damage caused by virus-induced nuclear rupture (81,122). Increased DNA damage and changes in the DNA damage response may lead to genomic changes or even genomic instability.…”

“…Defects in the nuclear lamina increase the frequency of nuclear envelope rupture, which exposes genomic DNA to cytoplasmic nucleases, damages DNA, and leads to genome instability (141). SARS-CoV-2 was shown to induce the cGAS-STING pathways because of the presence of cytoplasmic genomic DNAs, which are greatly increased by cell fusion (81,122). Interaction between the S protein and ACE2 can not only mediate virus entry, but also induce cell-cell fusion, resulting in the formation of syncytia -cells with multiple nuclei (142).…”

The nervous system during COVID‐19: Caught in the crossfire

“…129,130 Moreover, SARS-CoV-2 infection and syncytia of human lung pneumocytes and endothelial cells causes mitochondrial DNA release which stimulates the intracellular cGAS-STING pathway. [131][132][133] The stimulation of these PRRs in patients [134][135][136] and mice infected with mouse-adapted SARS-CoV-2 (MA10, MA30). 137,138 Therefore, there is mounting evidence that the dramatic stimulation of PRRs, especially TLR2, NLRP3, and cGAS-STING, early in infection is sufficient to drive COVID-19 immunopathology in the lungs.…”

“… 129 , 130 Moreover, SARS‐CoV‐2 infection and syncytia of human lung pneumocytes and endothelial cells causes mitochondrial DNA release which stimulates the intracellular cGAS‐STING pathway. 131 , 132 , 133 The stimulation of these PRRs in the lungs sets in motion a cascade of NF‐κB‐dependent signaling that leads to the potent and chronic release of pro‐inflammatory cytokines, including TNFα, IL‐1α, IL‐1β, IL‐6, and IL‐8—all of which are consistently elevated in the blood of hospitalized COVID‐19 patients 134 , 135 , 136 and mice infected with mouse‐adapted SARS‐CoV‐2 (MA10, MA30). 137 , 138 Therefore, there is mounting evidence that the dramatic stimulation of PRRs, especially TLR2, NLRP3, and cGAS‐STING, early in infection is sufficient to drive COVID‐19 immunopathology in the lungs.…”

Synergism of interferon-beta with antiviral drugs against SARS-CoV-2 variants

“…The S2' cleavage site appears to be essential to syncytia formation, with S1/S2 cleavage site enhancing this activity but not being essential to it. Removal of S2' sequence results in absence of cGAS-STING pathway activation (21).…”